Infection and immunity

A key outcome in medical education is the training of doctors to acquire the knowledge and understanding of the basic science that underpins clinical practice. The graduate will be able to apply to medical practice biomedical scientific principles, method and knowledge relating to: anatomy, biochemistry, cell biology, genetics, immunology, microbiology, molecular biology, nutrition, pathology, pharmacology and physiology .’ (Tomorrow’s Doctors 2009, GMC, UK). In this, the last of the themed chapters of questions that map to the Oxford Handbook of Medical Sciences, we will test knowledge of infectious diseases and the host immune responses that counteract them. Despite the shift of the world health problem to non-communicable diseases in recent times (Global status report on non-communicable diseases 2010, World Health Organization), infectious diseases remain a major health problem in many parts of the world. Even in developed countries, epidemics and outbreaks of infections are not infrequent events, pandemics sporadically crop up at the least expected times. In addition, microorganisms constantly evolve to escape the host immune response and to develop resistance to treatments that have been developed. Therefore, we have no choice but to keep up our knowledge and to develop new treatments.

Reproduction and development

Reproduction and development are large topics, knowledge of which underpins several medical specialities including sexual health, fertility, gynaecology, urology, reproductive endocrinology, obstetrics, and neonatology. Doctors need to know the structure, function, and endocrine control of both male and female systems in order to diagnose and manage conditions specific to either male or female organs, as well as conditions such as impotence and infertility. Not surprisingly, the reproductive system is the only body system that shows major differences in both structure and function between males and females. However, sexual differences go beyond the primary sexual characteristics present at birth and the secondary sexual characteristics that emerge under the influence of sex hormones at puberty. Sexual dimorphism in some brain structures commences at an early age, and differences in the endocrine profiles of males and females produce characteristic changes in morphology, physiology, and behaviour that go beyond simple sexual dimorphism to affect many aspects of life, including sexual differences in susceptibility to disease and the longer life expectancy of women as compared to men that is seen around the world. Whether these differences, mainly beneficial to women, are because females are ‘biologically superior’ or because of a complex mix of genetic, behavioural, and social factors is a matter for discussion and research. Some knowledge of embryology is important to every medical student. As a minimum it provides explanations for the congenital malformations and their consequences that are encountered in many areas of clinical practice. Deeper knowledge will assist those seeking real insights into the structure of the human body. It is the study of embryological development and the knowledge of how each tissue type arises, how one tissue meets another, and how tissues move and change shape during development that explains the relations between tissues and organs in the adult human form. Achieving a full understanding of the dynamics of the formation of the body’s organs and tissues is demanding, but it can replace some of the rote learning of anatomical structures, familiar to many students, with a deeper understanding of form and function.

Techniques of medical sciences

There are a limited number of laboratory techniques that underlie the large number of clinical investigations that are used routinely. Knowing and understanding the basis for these tests is essential in appreciating the clinical application of the various tests. Important parameters of clinical diagnostic tests are test sensitivity—how well are those with a condition correctly identified by the test and how low is the rate of false positives; and test specificity—how well does the test correctly identify those without the condition and what is the rate of false negatives. The cost-effectiveness of a test is also an important consideration. Familiarity with the underlying mechanisms will also help students and doctors to determine when to use the tests, to realize their value and limitations, and hence to exercise caution in interpretation. This chapter has questions that test knowledge of the mechanisms underlying a variety of techniques. Their application in clinical use is tested using a number of clinical scenarios.

Head and neck and neuroscience

Two apparently separate areas of medical science, head and neck and neuroscience, are often combined in the early phases of undergraduate medical education. Perhaps an obvious reason for this is that the brain, together with the organs of special sense — eyes, ears, nose, and taste buds — are located in the head. Head and neck injuries can therefore be serious and are commonly life-threatening. Another reason is embryological. The development of the head and the central nervous system (CNS) are closely intertwined. The whole CNS is essentially a segmented structure, with a pair of spinal (or cranial) nerves arising in each body segment. For the spinal cord and spinal nerves, each segment is marked by its own vertebra. The situation is more complex in the head, where the developing brain undergoes cervical, cephalic, and pontine flexures. These folds in the growing neural tube, plus the development of a protective cranium, obscure the underlying segmental pattern, but each segment of the brain still bears its pair of cranial nerves. The organization of the CNS and peripheral nervous system is complex but ordered, and neurological disorder can often be diagnosed by a process of clinical reasoning if the structural and functional properties of the system are sufficiently well understood. Neurological disorders commonly present as alteration in, or loss of, sensation or disturbance of motor function. Knowing which areas of skin (the dermatomes) and which muscles are innervated by each cranial or spinal nerve, together with understanding the characteristic deficiencies produced by abnormality, will often allow the neurologist to use clinical reasoning skills to localize a lesion with considerable accuracy, before radiological or other investigation is undertaken. The diagnostic process is assisted by specific neurological tests, performed during the physical examination, which investigate the integrity of various neural pathways. Disorders of the CNS can involve alterations of sensory perception, motor performance, emotion, overt behaviour, consciousness, and perceptions of self. Some diagnoses may be made with neurological techniques, others by psychiatric techniques, and in many instances the recognition of characteristic patterns of altered perception, performance, or behaviour may be important clues.

Digestive system

In essence, the digestive system is a four-layered tube that extends from mouth to anus. Its main purpose is the enzymatic digestion of food to produce smaller molecules that can then be absorbed into the body as nutrients. To achieve this the gut is regionally specialized to enable the serial processing of food and the absorption of food, water, and electrolytes as materials pass along the bowel. The four layers of the bowel are: 1) A mucosa surrounding the lumen, made up of a specialized epithelium, a lamina propria of connective tissue, and a layer of smooth muscle—the muscularis mucosae. 2) A submucosa, a layer of connective tissue oft en containing glands. 3) A muscularis externa with, usually, an inner layer of circular smooth muscle and an outer layer of longitudinal smooth muscle, responsible for peristalsis. 4) An outermost layer of epithelia and connective tissue called the adventitia, or serosa if the bowel is enfolded by peritoneum or mesentery. Despite this common arrangement along the whole bowel, the four layers show characteristic differences in each region, reflecting the specialization of function found in the oesophagus, stomach, small intestine, and large intestine. Indeed, differences can also be seen between the subdivisions of these regions. Associated with the gut are two major organs, the liver and the pancreas. The liver processes the newly absorbed nutrients passed to it from the bowel by the hepatic portal vein. It also produces bile, which is eventually secreted into the bowel. Bile, stored and modified between meals in the gallbladder, is a vehicle for the removal from the body of conjugated bile pigments from the breakdown of haemoglobin. Bile also delivers to the small intestine the bile salts essential for the proper digestion of fats. The pancreas is divided into an exocrine pancreas, whose secretions of pro-enzymes, bicarbonate, and water pass to the small intestine to neutralize gastric acid and support digestion, and islets of endocrine tissue that produce insulin, glucagon and somatostatin — hormones concerned, in part, with glucose regulation. Control of bowel function is complex.

Molecular and medical genetics

Genetics has come a long way since the pioneering work on plant inheritance patterns by the Augustinian monk, Gregor Mendel, in the mid-nineteenth century. In the first decades of the twentieth century, Archibald Garrod, a London physician, was studying a class of diseases which came to be called ‘inborn errors of metabolism’. As a result of studies on conditions such as alkaptonuria (a rare disease involving altered phenylalanine and tyrosine metabolism, with production of dark urine and a rare form of arthritis), Garrod postulated the ‘one gene – one enzyme’ hypothesis, namely that most inborn errors of metabolism result from errors in single genes that code for enzymes. This showed remarkable foresight, since the actual nature of DNA and the way genes are transcribed and translated was not fully established until the work of Watson and Crick and others in the 1950s and beyond. One gene – one enzyme (or one protein) has now been modified to become one gene – one peptide, but the principle holds. As more has been learned about human genetics and genetic mutation, especially following the Human Genome Project, the number of genetic defects known to underpin diseases and predisposition to disease has burgeoned. All this new knowledge is adding to earlier knowledge of diseases that were detected by studying chromosome number (cytogenetics) or by examining family pedigrees for the patterns of disease inheritance. Studies of family pedigrees exposed the genetic nature of diseases as diverse as cystic fibrosis, haemophilia, sickle-cell disease, and Huntington’s disease. Nowadays, a doctor’s training in medical genetics will cover the genetic code, gene expression, gene regulation and mutation, cancer genetics, chromosomal abnormalities, abnormalities at the gene level, genetic polymorphism, the principles of gene therapy, and the emerging science of pharmacogenetics. As it has become evident not only that diseases are a direct expression of particular genes or mutations, but that genetic predisposition can be identified for a great number of diseases, both ethical and therapeutic questions arise. For example, will every healthy person want or need to have knowledge of his or her own future risk for specific diseases? To what extent will gene therapies or pharmacogenetics have to be tailored to an individual’s genetic constitution, and at what financial cost?

Cell Structure And Function

Almost every medical student in the United Kingdom, and in many other countries, begins his or her studies with a course on basic cellular structure and function. Such courses are often designed to help students from a variety of educational backgrounds to appreciate the concepts and vocabulary central to all of the life sciences. Over time this core knowledge will be supplemented by other, more specific, areas of medical science until the point is reached at which learners can apply their scientific understanding to those processes of clinical reasoning that lead to diagnosis and treatment. Medical science assists the process of diagnosis by explaining how underlying disease states produce characteristic symptoms and signs. It also facilitates safer treatment by explaining many of the properties, both beneficial and deleterious, of the increasing range of oft en potent therapeutic agents used in clinical management. This chapter poses questions about the basic chemicals of life: proteins, lipids, and carbohydrates. It also covers significant features of the cell membrane and cellular organelles as well as cell division, cellular differentiation, and cell death. Understanding the basic principles of intracellular and intercellular communication and regulation provides the foundation for appreciating the role that these processes play in normal and abnormal neural and hormonal control, which will be considered in more detail in later chapters. All of these topics will eventually contribute to a medical student’s grasp of normal structure and function and how it becomes disturbed in disease. The current chapter also includes questions on basic pharmacokinetics. Knowing how each drug works — that is to say its kinetics and mode of action — is a first step in learning to prescribe safely. Other important principles will be added later in the medical student learning process: for example, the indications and contraindications for the use of a drug; any unwanted side-effects; the route of administration and dosages to produce optimal effects. All of this information must be mastered to help prevent the prescribing errors that are all too common in clinical practice.

Clinical application of medical sciences

This chapter comprises a mixture of questions overlapping in content with those in the preceding 14 chapters, but often at a higher level, testing the understanding and application of basic science in clinical medicine. As such, students in the earlier years of the medicine course should leave this section until you have attempted questions in most of the other chapters. However, senior medical students or newly qualified doctors who may be using this book to revise for postgraduate examinations should feel more confident in this section. Since the questions are a mixture, and represent a sample of many areas of basic science, we will use it to show how an exam paper is set. Of course, students should realize that there may be some variation between medical schools, but some broad principles will still apply. The team or person organizing the exam will initially design an exam blueprint. The blueprint is determined by the learning objectives and skills to be tested, and the relative importance of each, expressed as relative percentages or number of questions. Usually, these are proportional to the amount of time allocated to the topics in the curriculum. This will ensure that there is adequate coverage and sampling of the learning objectives. The blueprint consists of a table showing the content and allocation of questions. The table may be very detailed, in which case there will not be many questions in each category, or it may be rather more broad. In an integrated medical exam, the contents usually reflect body systems and tasks or skills. Some blueprints may also include traditional subject areas such as anatomy, pathology, and pharmacology to make sure that these are not under-represented. An example is shown overleaf. Some of the categories are somewhat artificial as they are intimately related. For example, some questions that are entered under ‘diagnosis’ require ‘interpretation of laboratory data’. Some questions that test management require a student to make the diagnosis beforehand. Once the blueprint is set, question writers are then directed to populate the question paper accordingly.

Endocrine system

Complex animals have evolved two separate systems for the control of body tissues. One is the nervous system, which makes direct connections with specific muscles and glands and regulates their activity by the focal release of neurotransmitters. The other system is the endocrine system, where hormones, secreted into the circulation, can exert effects on remote tissues in many different locations simultaneously. The classical distinction between the two systems is, however, blurred. Some hormones, such as antidiuretic hormone and oxytocin, are released into the bloodstream by neurones, rather than by typical endocrine cells. In other situations, hormones are released only to act locally, not all over the body, as with paracrine cells. Occasionally, the hormone feeds back on to the cell that secreted it, as in autocrine regulation. The interface between neural and endocrine control lies in the hypothalamus and related areas of the brain. This region also helps integrate the output of the autonomic nervous system, which controls visceral function. Hypothalamic areas also regulate appetite behaviours for food, water, sex, etc. Autonomic nervous system, appetites, and hormones all contribute to homeostasis — the regulation of the internal environment of the body. The hypothalamus and the pituitary gland form the ‘hypothalamic–pituitary endocrine axis’. This axis regulates much of the body’s endocrine activity through a system of hypothalamic factors. These factors, which are hormones in their own right, regulate the release of individual pituitary hormones. Each pituitary ‘trophic’ hormone then controls a part of the overall endocrine system. Thus, pituitary hormones control hormone production by thyroid, adrenal cortex, liver, and gonads. This complex cascade of hormonal control is regulated by various types of negative feedback based on plasma hormone concentrations. The hypothalamus and pituitary are also controlled by higher centres in the brain. Other endocrine tissues also use negative feedback control, but rather than the level of the hormone itself, it is the level of stimulus that regulates hormone secretion. Thus, rising plasma osmolarity (or decreasing blood volume) stimulates antidiuretic hormone secretion, and rising plasma glucose stimulates insulin secretion. Combinations of hormones are sometimes used to regulate an aspect of the internal environment. The control of plasma calcium by calcitonin, parathormone, and calcitriol (1,25-dihydroxycholecalciferol), and of plasma glucose by insulin and glucagon, are examples.

Respiratory and cardiovascular system

Oxidative metabolism is essential for our cellular life. Although tissues such as skeletal muscle can operate for short periods anaerobically, human life does not continue for long in the absence of a ready supply of oxygen. Adequate oxygen delivery to tissues is essential for aerobic metabolism and disorders of delivery ultimately become life-threatening. The factors contributing to oxygen delivery are summarised in the oxygen flux equation: OXYGEN FLUX = CARDIAC OUTPUT × ARTERIAL OXYGEN CONTENT The cardiac output is the product of heart rate and stroke volume and amounts to about 5 litres per minute. The arterial oxygen content is the product of the blood’s haemoglobin concentration multiplied by the haemoglobin’s % saturation. The latter is determined by the partial pressure of oxygen in the blood. This is higher in arterial than in venous blood. A small, additional amount of oxygen is carried dissolved in the blood, the amount again determined by the oxygen partial pressure. The five litres of arterial blood delivered to the tissues each minute contain about 1000ml of oxygen. Only a quarter of this (250ml) is needed to support resting metabolism. There is therefore a large safety factor in oxygen delivery. This can be utilized, in concert with adaptive changes to cardiac output, vascular resistance and pulmonary ventilation, in situations such as muscular exercise, where oxygen demand increases dramatically, or at high altitude where inspired oxygen is low. Oxygen delivery depends on the cardiovascular system, respiratory system and the blood. In the lungs, blood in the alveoli is brought into close proximity with alveolar air so that oxygen can diffuse easily into the blood and carbon dioxide, a major waste product of metabolism, can diffuse into the alveolar air. Alveolar air is kept refreshed with atmospheric air by pulmonary ventilation which keeps the partial pressures of oxygen and carbon dioxide in alveolar air and pulmonary capillary blood in a constant equilibrium. This process ensures that pulmonary venous blood and systemic arterial blood have high oxygen and low carbon dioxide partial pressures. Once in the blood, almost all of the oxygen combines with haemoglobin and is transported by the cardiovascular system to the tissues.